Rapid pain modulation with nuclear receptor ligands.
Rapid pain modulation with nuclear receptor ligands.
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DOI：
10.1016/j.brainresrev.2008.12.019
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发表时间：
2009-04
影响因子：
--
通讯作者：
Taylor BK
中科院分区：
文献类型：
--
作者：
Fehrenbacher JC;Loverme J;Clarke W;Hargreaves KM;Piomelli D;Taylor BK
我们讨论并提出了关于核受体激活在疼痛控制中的生理和分子机制的新数据，特别强调了过氧化物酶体增殖激活受体（PPAR）、GPR30和经典雌激素受体的配体的非基因组效应。在许多疼痛试验中，PPARα激动剂可迅速减轻急性和慢性疼痛。这些作用先于转录抗炎作用，部分由DRG神经元上的IKca和BKca通道介导。与PPARα配体的外周作用部位相反，背角支持PPARγ的表达。鞘内给药PPARγ配体迅速（≤5分钟）以剂量依赖的方式减弱与神经损伤相关的机械和热超敏反应，可被PPARγ拮抗剂阻断。相比之下，PPARγ拮抗剂本身迅速增加与神经损伤相关的机械异常性痛。这些数据表明，脊柱PPARγ的配体依赖性非基因组激活可减少炎症性和神经性疼痛的行为体征。我们还报道了GPR30在培养的感觉神经元上表达，受体的激活引发信号传导增加钙积累和PKCε易位，并且这种信号传导可能有助于增加神经元敏感性，因为GPR30激动剂治疗诱导痛觉过敏。最后，应用膜不渗透性17ß-E2-BSA迅速（在15分钟内）增强bk刺激的肌醇磷酸（IP）积累和pge2介导的三叉神经节cAMP积累。我们得出结论，核受体配体可能通过快速，非基因组机制来调节炎症和神经性疼痛。
We discuss and present new data regarding the physiological and molecular mechanisms of nuclear receptor activation in pain control, with a particular emphasis on non-genomic effects of ligands at peroxisome proliferator-activated receptor (PPAR), GPR30, and classical estrogen receptors. PPARα agonists rapidly reduce both acute and chronic pain in a number of pain assays. These effects precede transcriptional anti-inflammatory actions, and are mediated in part by IKca and BKca channels on DRG neurons. In contrast to the peripheral site of action of PPARα ligands, the dorsal horn supports the expression of PPARγ. Intrathecal administration of PPARγ ligands rapidly (≤5 minutes) attenuated mechanical and thermal hypersensitivity associated with nerve injury in a dose-dependent manner that could be blocked with PPARγ antagonists. By contrast, a PPARγ antagonist itself rapidly increased the mechanical allodynia associated with nerve injury. These data suggest that ligand-dependent, non-genomic activation of spinal PPARγ decreases behavioral signs of inflammatory and neuropathic pain. We also report that the GPR30 is expressed on cultured sensory neurons, that activation of the receptor elicits signaling to increase calcium accumulation and PKCε translocation, and that this signaling may contribute to increased neuronal sensitivity as treatment with the GPR30 agonist induces hyperalgesia. Finally, application of the membrane-impermeable 17ß-E2-BSA rapidly (within 15 min) enhanced BK-stimulated inositol phosphate (IP) accumulation and PGE2-mediated cAMP accumulation in trigeminal ganglion cultures. We conclude that nuclear receptor ligands may operate through rapid, non-genomic mechanisms to modulate inflammatory and neuropathic pain.
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DOI：
10.1073/pnas.91.18.8517
发表时间：
1994-08-30
影响因子：
11.1
作者：
ARONICA, SM;KRAUS, WL;KATZENELLENBOGEN, BS
通讯作者：
KATZENELLENBOGEN, BS
影响因子：
2.7
作者：
Bennett, HL;Gustafsson, JÅ;Keast, JR
通讯作者：
Keast, JR
DOI：
10.1046/j.1432-1033.2002.02912.x
发表时间：
2002-05-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Ahola, TM;Purmonen, S;Ylikomi, T
通讯作者：
Ylikomi, T
影响因子：
2.7
作者：
Brown, PJ;Stuart, LW;Willson, TM
通讯作者：
Willson, TM
影响因子：
7.4
作者：
Fehrenbacher, JC;Burkey, TH;Vasko, MR
通讯作者：
Vasko, MR